Phenoxyalkylamines, process for their preparation and applications thereof

ABSTRACT

This invention relates to phenoxyalkylamines having the formula:   IN WHICH N IS ZERO OR 1, R is hydrogen or a hydroxy group, R2 is hydrogen, a hydroxy group or an alkyl group, R2 being other than hydroxy when n is zero, A is a group   BEING HYDROGEN, A CYCLOALKYL GROUP OR AN ARYL GROUP. Said phenoxyalkylamines possess coronary vasodilator and cardiotonic properties.

United States Patent [191 Pinhas 111 3,873,620 [451 Mar. 25, 1975 1 1PHENOXYALKYLAMINES, PROCESS FOR THEIR PREPARATION AND APPLICATIONSTHEREOF [75] Inventor: Henri Pinhas, Paris. France [73] Assignee:Laboratoires Laroche Navarron,

Levallois, France [22] Filed: Dec. 20, 1971 [21] Appl. No.: 210,107

[30] Foreign Application Priority Data Dec. 28, 1970 France 70.46875[56] References Cited UNITED STATES PATENTS 3,278,601 10/1966 Moed260/5706 3.437.731 4/1969 Schmitt et a1 260/5707 X 3.501.769 3/1970Crowther et ul 260/5707 X 3.644,469 2/1972 Koppe et a1. 260/5707 XPrimary Examiner-Robert V. Hines Attorney, Agent, or Firm-Oldham &Oldham Co.

1 1 ABSTRACT This invention relates to phenoxyalkylamines having theformula:

T2 a U in which n is zero or 1, R is hydrogen or a hydroxy group, R ishydrogen, a hydroxy group or an alkyl group, R being other than hydroxywhen n is zero, A is a group I -C-R or -C-R R II I 1 0 on beinghydrogen, a cycloalkyl group or an aryl group. Said phenoxyalkylaminespossess coronary vasodilator and cardiotonic properties.

2 Claims, N0 Drawings PHENOXYALKYLAMINES, PROCESS FOR THEIR PREPARATIONAND APPLICATIONS THEREOF COR R-CH

- ca (CH NH on group, R, is an alkyl group and R is hydrogen, a hydroxygroup or an alkyl group, R being other than hydroxy when n is equal tozero, or a product resulting from hydrogenation of the ketone group COR,thereof to an alcohol group CHOHR The vasodilatator and spasmolyticproperties of said prior phenoxyalkylamines were found to be quiteoutstanding;

However, there have been found new phenoxyalkylamines which, whilehaving still better vasodilatator and spasmolytic properties than thosealthough already exceptional of the prior phenoxyalkylamines, have abetter therapeutic ratio than the latter. Phenoxyalkylamines wereprepared which exhibit toxicity only at dosages above 500 mg andsometimes up to 1,500 mg under the same experimental conditions as thosementioned above.

Said new phenoxyalkylamines according to the invention have the formulaThe phenoxyalkylamines of this invention may also exist in the form ofacid addition salts thereof with inorganic or organic acids andtypically as the hydrohalides, particularly the hydrochlorides andhydrobromides, as the nitrates, sulfates, methanesulfonates, lactates,citrates, maleates, tartrates, acetylsalicylates, acetates, oxalates,and the like salts which are readily prepared by reacting compounds (I)as the free base with stoichiometrically equivalent amounts of theselected acid or acids.

CH 3 H N CH CH 1; biidfisd" as; a 5555a; massage 115mg the formula(ITII) O-CH -Z in which Z is a radical selected from the radicals CH2 CH(CH NH ca CH3 in which n is zero or 1, R is hydrogen or a hydroxy group,R is hydrogen, a hydroxy or alkyl group, R being other than hydroxy whenn is zero, A is a group I E-R or 43-11 R being hydrogen, a cycloalkylgroup or an aryl group.

In the above definition, the alkyl radicals are advantageously lowerradicals, having typically from I to 12 carbon atoms and preferably from1 to 6 carbon atoms.

When R is an aryl group, it is advantageously a phenyl group, while thepreferred cycloalkyl ring is cyclo hexyl.

-cn CH2 and -cm (A --o--R if desired, to the alcoholicphenoxyalkylamines The phenoxyalkylamines (l) in which R is hydrogen areobtained from compounds (III) in which Z is a radi cal CH (CH ),,-X.

The phenoxyalkylamines (l) in which R is an alkyl radical are obtainedfrom compounds (ill) in which Z is either a radical belli h"lkyir'dibal. art" raaiza'a' it being understood that in the latter case itis convenient to reduce suitably the double bond formed in the chain.

When group Z represents the group -CH CH the condensation reaction givesrise to ph'nb'x' 'iit 'i mines hydroxylated in their chain.

It is generally advantageous to conduct the condensation under refluxingconditions within an alcohol solvent, e.g., within ethanol in thepresence of triethylamine or other basic agents. When intermediate (Ill)possesses a ketone function in the side-chain, it is preferred to use abenzene solvent and to remove the water formed during the condensation.In the latter case, the double bond formed in the chain may then besaturated by means of a mild reduction, for example by the catalyticroute in the presence of palladium-oncharcoal to give compounds (I) inwhich A is ketonic.

Whether such ketonic compounds are obtained directly by condensation orare derived from a condensation followed by a reduction, as explainedabove, they may be reduced to their alcoholic homologs I (A --C-R1) bythe catalytic route, typically in the presence of platinum oxide orother metal catalysts, and preferably with a metal borohydride such assodium or potassium borohydride, within an alcohol solvent such asmethanol.

When the condensation products unsaturated in the chain are reduced witha borohydride, not only is the double bond reduced, but also the ketonefunction included in A, so that the alcoholic phenoxyalkylamines areobtained directly.

Intermediates (III) are obtained by reacting a phenol compound of theformula with a halogenated compound Y CH Z EXAMPLE I.

4-12-(oz-methyl-phenethylamino)-ethoxylcyclohexanophenone A COR -CO-C ,HR R H; 1 O

a. 4-(2-bromo-ethoxy)-cyclohexanophenone is first preparedp-hydroxy-cyclohexanophenone (0.5 mole) is dissolved in water (700 ml)containing sodium hydroxide (0.5 mole). 1,2-dibromo-ethane (0.6 mole) isadded to the refluxing solution.

The solution is refluxed during twenty hours, and is then allowed tocool. It is extracted with diethyl ether, and is then washed with dilutesodium hydroxide and then with water.

The ether phase is dried, concentrated, and the residue is thendistilled b.p. 202-206C 2-(2-bromo-ethoxy)-cyclohexanophenone isprepared using the above procedure b. A solution ofa-methyl-phenethylamine (1 mole), 4-(2-bromo-ethoxy)-cyclohexanophenone(l mole) and triethylamine (3 moles) in ethanol (600 ml) is refluxedduring 48 hours. The solvent is removed in vacuo. The residue isdissolved in an organic solvent (such as diethyl ether or ethylacetate). A 10 hydrochloric acid solution is added with vigorousstirring. The crystals are suction filtered and are then recrystallizedfrom methanol (Yield to give 4-[2-(amethyl-phenethyl-amino)-ethoxy]-cyclohexanophenone hydrochloride, m.p. l77l79C.

The procedure described above is used with the ortho derivative, to give2-[2-(a-methylphenethylamino)-ethoxy]-cyclohexanophenone, m.p. -l62C.Yield 60 EXAMPLE 2.

droxyamethyl-phenethylamine. The yield is 70 and the hydrochloride meltsat 170172C.

EXAMPLE 3.

1-[( l-cyclohexyll -hydroxy)-methyl ]'4-[Z-(amethyl-phenethylamino)-ethoxy]-benzene and its hydrochloride:

A Jill-C 14 R R R R H; n 0

Potassium borohydride (0.12 mole) is gently added to4-[2-cx(-methyl-phenethylamino)-ethoxy]- cyclohexanophenone (0.1 mole)dissolved in 90 methanol (150 ml). at a temperature below 0C.

After 15 hours. the methanol is removed at -30C, in vacuo. The residueis taken up into water and ether. The organic phase is thoroughly washedwith water. The ether phase is dried and evaporated. The residue isconverted to the hydrochloride. in the usual manner.

The white crystals recrystallize from alcohol/ether.

M.p. l74*175C Yield 90 EXAMPLE 4.

4-[2-(a-rnethyl-phenethylamino)-ethoxy]- EXAMPLE 51-[a-hydroxy-benzyl]-4-[2-(oz-methylphenethylamino)-ethoxy]-benzene andits hydrochloride.

4-[2-(a-methyl-phenethylamino)-ethoxy]- benzophenone is reduced in theusual manner with potassium borohydride.

Treatment as in Example 1 giveshydroxybenzyl]'4[2-(a-methyl-phenethylamino)- ethoxy]-benzenehydrochloride (92 m.p. l65l68C.

EXAMPLE 6 4-[ 2-hydroxy-3-( a-methyl-phenethylamino)-propoxy]-cyclohexanophenone.

4-(2,3-epoxy-propoxy)-cyclohexanophenone is first prepared. For thispurpose, para-hydroxycyclohexanophenone (0.1 mole) is dissolved in 5 sodium hydroxide (0.1 mole); 1-chloro2,3-epoxypropane (0.11 mole) is addedto the stirred solution, over one hour.

After 24 hours, the resulting crystals are suction filtered, and arethen washed with water and dried.

The residue is distilled: hp 180-l86C; yield a-methyl-phenethylamine(0.1 mole) and 4-(2,3- cpoxy-propoxy)-cyclohexanophenone (0.1 mole) arethen refluxed during four hours in alcohol ml). The solvent is removedin vacuo. The residue is taken up into diethyl ether. 5 hydrochloricacid in then added thereto.4[2-hydroxy-3-(a-methylphenethylamino)-propoxy]-cyclohexanophenoneprecipitates out on vigorous stirring. It is recrystallized fromethanol. M.p. 174-l77C.

EXAMPLE 7 The ketone function of the above described product (Example 6)is reduced with borohydride, in the usual manner, to give l-[(l-cyclohexyl-l-hydroxy)-methyl]-4-[2-hydroxy-3-(a-methyl-phenethylamino)-propoxy]- benzenehydrochloride. M.p. 136C.

EXAMPLE 8.

4[2-(a-methyl-phenethylamino)-propoxy]- cyclohexanophenone.

para-Hydroxy-cyclohexanophenone (0.1 mole) and sodium hydroxide (0.1mole) are dissolved in 80 alcohol (100 ml).

Chloroacetone (0.12 mole) is added dropwise to this solution.

After refluxing during seven hours, the reaction mixture is concentratedin vacuo. It is then extracted with ether, washed with 5 sodiumhydroxide and then with water.

The residue is then distilled b.p. r, 182l87C. Yield 72 "/0.

4-(2-oxo-propoxy)-cyclohexanophenone (0.02 mole) anda-methyl-phenethylamine (0.02 mole) are then heated in benzene solution.The water formed is removed by means of a Dean-Stark apparatus.

The solvent is removed in vacuo and the residue is hydrogenated in thepresence of 5 palladium-oncharcoal, in alcohol solution. at roomtemperature. under 2 kg hydrogen pressure.

The alcohol is removed. The residue is taken up into ether, andabundantly washed with water. The ether phase is dried and thenconcentrated, after which the hydrochloride is prepared. M.p. 130134C.

EXAMPLE 9 1-hydroxymethy1-4-[2-(oz-methyl-phenethylamino)-ethoxy]-benzene.

CH OH; R R H; n O

4-( 2-bromo-ethoxy)- 1 -hydroxymethyl-benzene is first prepared from4-hydroxymethyl-phenol and 1,2- dibromoethane, using the same procedureas in Example 1. This bromo derivative is then condensed witha-methyl-phenethylamine, to give 1-hydroxymethyl-4-[2-(a-methyl-phenethylamino)-ethoxy]-benzene hydrochloride in a 50yield. M.p. I36-I38C.

The results of toxicological and pharmacological tests demonstrating thesafe character and the activity of the phenoxyalkylamines of thisinvention are given below.

I. ACUTE TOXICITY The acute toxicities of said materials wereinvestigated orally, in Swiss mice and Sprague Dawley rats.

The animals are fasted eighteen hours prior to the single administrationof the product and are kept under supervision forteen days during whichtheir behavior and death rate were noted.

The LD of said products, investigated in both species and calculatedaccording to the method according to Litchfield and Wilcoxon are of theorder of from 500 to 1,500 mg/kg.

II. CORONARY DILATATOR ACTION 1. On the isolated heart Langendorffsmethod.

The tests were carried out on the hearts of Fauve de Bourgogne (about 2kg) rabbits. The hearts are rapidly taken out and maintained insurviving condition by perfusion ofa physiological (Tyrode type) liquidheated at 37C and oxygenated under a constant pressure of 50-60 cm ofwater. Perfusion of the hearts were effected counter-currently, andvolumetric determinations of the coronary rate of flow were recorded at30 second intervals.

After stabilization of the basic rate of flow, the products, dissolvedin physiological saline solution, are injected in a volume of from 0.05to 0.2 ml.

The products produce a marked increase of the coronary rate of flowwhich is apparent at a dosage of 10 'y; a 50 increase of the originalrate of flow is obtained, depending on the test products, at a dosagecomprised within the range from y to 100 y.

2. On the whole animal 1 The tests were carried out in male and femaledogs having a weight between 10 and 15 kg.

After chloralose-induced anesthesia, the animals are placed underartificial respiration.

The carotid pressure is recorded, together with the cardiac frequencyand the electrocardiogram.

The coronary flux is investigated by means ofa nycotron.

The test materials were dissolved in physiological saline solution andadministrated by the intravenous route.

Increase of the coronary flux is observed at dosages from 0.5 to 2mg/kg.

III. ACTION ON CONTRACTILE STRENGTH The tests were carried out either inthe whole animal, or in the isolated heart.

Dogs, both male and female, are anesthetized with chloralose.

Systemic blood pressure is recorded at the level of the carotid with anelectric sensor.

The contractile strength of the heart was measured with a strain gaugeattached to the wall ofthe right ventricle.

The products, dissolved in physiological saline solution, areadministrated intravenously (external saphenous vein).

The phenoxyalkylamines of this invention produce an increase of thecontractile strength of the heart which becomes more marked with time.Generally, this action has a duration of over one hundred minutes. Thecardio-tonic action is apparent at dosages from 0.5 to 2 mg/kg.

The products were tested on the isolated heart of rabbit maintained insurviving condition by Langendorffs method. The contractile strength ismeasured by means of a strain gauge attached to the right ventricle.Cardiac stimulation is apparent at dosages of about 200 y.

IV. SPASMOLITIC ACTION The spasmolytic action was studied in vitro witha fragment of duodenum of rat maintained in surviving condition in anoxygenated physiological liquid. Inhibition of 50 of the contraction dueto effusion of a given dose of acetylcholine and barium was studied. TheED of the test products is comprised within a range from 20 to 65 'ywith respect to acetylcholineinduced contraction, and within a rangefrom 15 to "y with respect to barium-induced contraction.

It is apparent from such tests that the phenoxyalkylamines of thisinvention and their non-toxic salts are useful in human therapeutics forthe curative or preventive treatment of heart conditions, as coronaryvasodilatator, cardiotonic and spasmolytic drug.

In such applications, the therapeutic composition is advantageouslyadministered orally, at a dosage of from to 750 mg of active ingredientper 24 hours.

Any formulations suitable for this route of administration may be used,the active ingredient being admixed with a pharmaceutically acceptablecarrier or excipient.

An example of such a formulation is given:

An example of such a formulation is given Tablets containing each: 50 mg(average dose) I00 mg (strong dose) Talc Lactose Mg stearate, q.s. tomake 1 tablet.

Excipients:

\ co CH2 ca (ca l r NH CH CH is an integer selected l, R# selected fromthe group consisting of hydrogen, and methyl, A is selected from thegroup consisting of the radicals l C and C u O OH and theirnon-toxicacid addition salts. V

2. 4-[2-(a-methyl-phenethylamino-ethoxy)]- cyclohexanophenone.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF PHENOXALKYLAMINES OFFORMULA
 2. 4-(2-( Alpha-methyl-phenethylamino-ethoxy))-cyclohexanophenone.